An incomplete understanding of the molecular perturbations that cause disease, as well as a limited arsenal of robust model systems, has contributed to the failure to generate successful disease-modifying therapies against common and progressive neurodegenerative diseases (ND), such as Parkinson's Disease (PD) and Alzheimer's Disease (AD). These limitations, combined with commonly-assumed restrictions on the “druggable” proteome, present a major challenge for target-based drug discovery. Despite the predominance of this strategy, in the past 15 years, unbiased phenotypic screens have identified greater than 50% more new chemical entities with new mechanisms of action (MOA) than target-based screens (1). This success has sparked renewed interest in unbiased cell-based screens for compounds that work in unanticipated ways (2). In the context of NDs, establishing neuronal screening platforms is exceptionally challenging (3). However, when neuronal pathologies derive from perturbations of conserved eukaryotic processes, simpler cell-based models offer a potential solution. Modeling the cellular pathologies that underlie α-synucleinopathies (including PD) in yeast recapitulates the derangements in protein trafficking and mitochondrial dysfunction that are seen in neurons and PD patients (4). The ease of yeast culture and the robust growth phenotypes induced by α-synuclein greatly facilitate high-throughput compound screening (3, 4). While phenotypic screens are unbiased, the formidable challenge of deciphering MOA can limit the advancement of lead compounds by impeding target-guided medicinal chemistry and early clinical evaluation of on-target efficacy. Therefore, there is a need to identify compounds that address underlying cellular pathologies in NDs and to define the specific target space in which they act.